tbuckley/cabot-search huggingface dataset:
NIMG-83. MULTIMODAL PET/MRI RADIOMICS AND CLINICAL PARAMETERS FOR OVERALL SURVIVAL PREDICTION IN PATIENTS WITH IDH WILDTYPE GLIOBLASTOMA
Authors: Robin Gutsche, Elena Bauer, Martin Kocher, Jan-Michael Werner, Gereon Fink, Nadim Shah, Karl-Josef Langen, Norbert Galldiks, Philipp Lohmann
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Currently, most radiomics studies on survival prediction in brain tumor patients are based on MRI only. The goal of our study was to evaluate multimodal radiomics derived from amino acid PET/MRI and clinical parameters for survival prediction in patients with newly diagnosed IDH wildtype glioblastoma. METHODS Sixty-three patients with newly diagnosed IDH wildtype glioblastoma were evaluated retrospectively. At initial diagnosis, all patients underwent structural MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET. Tumor volumes were automatically segmented using a deep learning-based tool followed by visual inspection. Predefined and deep radiomics features were extracted from both imaging modalities. Feature repeatability analyses and feature selection were performed to avoid overfitting. Cox regression models for overall survival were built from clinical parameters such as age or the extent of resection, radiomics features, and combinations thereof, and finally validated using 5-fold cross-validation. Further evaluation of the model in an external test dataset is ongoing. RESULTS The median overall survival was 12 months (range, 0-64 months). Higher age and larger FET PET tumor volumes were significantly correlated with shorter overall survival (age, r=-0.39, p&amp;lt; 0.001; volume, r=-0.31, p&amp;lt; 0.05). Models solely based on predefined FET PET or MRI radiomics features showed a similar mean concordance index (C-index) as the model based on clinical parameters (C-indices, 0.68±0.04; 0.64±0.03; and 0.69±0.08, respectively). Multimodal radiomics based on predefined and deep features yielded improved C-indices of 0.75±0.06 and 0.72±0.09, respectively. A model based on multimodal radiomics and clinical parameters achieved the best prognostic performance (C-index, 0.80±0.04). CONCLUSION Our results suggest an added clinical value of multimodal FET PET/MRI radiomics with clinical parameters for the non-invasive survival prediction in patients with IDH wildtype glioblastoma.
INNV-04. PRIMARY TREATMENT OF SMALL-TO-MEDIUM(&amp;lt; 3CM) SPORADIC VESTIBULAR SCHWANNOMAS: SYSTEMATIC REVIEW &amp; META-ANALYSIS (2010 TO 2020)
Authors: Amey Savardekar, Danielle Terrell, Saudamini LeLe, Jennifer Kosty, Chiachien Jake Wang, Bharat Guthikonda
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Over the past two decades, the treatment of small-to-medium (&amp;lt; 3cm) sporadic vestibular schwannomas (VS) has experienced a definite shift to stereotactic radiosurgery vis-a-vis microsurgery. We performed a systematic review and meta-analysis of VS patients primarily treated with stereotactic radiosurgery (SRS) or microsurgery (MS), with particular attention to hearing preservation outcomes (HPO), tumor control (TC), and facial nerve dysfunction (FND). Materials and METHODS A systematic review was conducted (Medline database) for the period, 2010 to 2020. Studies with mean/median follow-up of &amp;gt;/= 3 years were included. Studies had to report an acceptable standardized hearing metric. HPO, TC, and treatment complications (with special attention to FND) were compared between the MS and SRS groups. RESULTS Thirty-two studies met our inclusion criteria: 10 for microsurgery and 23 for radiosurgery (one comparative study included in both arms). HPO were comparable between MS group and SRS group (56% and 59%, p=0.1527). TC was significantly better in MS group (98%) versus SRS group (92%) [p &amp;lt; 0.0001]. FND was significantly higher in MS group (11%) versus SRS group (2%) [p &amp;lt; 0.0001]. CONCLUSION The ability to diagnose small sporadic VS earlier, allows patients time to consider all possible treatment options which include observation, radiosurgery, or microsurgery. The data presented in this study will assist physicians in their ability to appropriately counsel patients on the benefits and risks of both treatment modalities with the most recent evidence on the factors that contribute greatly to patients’ quality of life: HPO, TC and FND.
BIOM-54. ANALYTICAL VALIDATION OF A TARGETED GENE EXPRESSION BIOMARKER PREDICTING MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES
Authors: William Chen, Calixto-Hope Lucas, Abrar Choudhury, Harish Vasudevan, Stephen Magill, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Improvements in meningioma risk stratification are needed to guide postoperative management. We previously developed and externally validated a targeted gene expression biomarker predicting meningioma outcomes and radiotherapy response using fresh frozen meningiomas. Here, we present the analytical validity, test-retest and cross-platform reproducibility, intra-tumor heterogeneity, and formalin fixed paraffin embedded (FFPE) concordance for this biomarker. METHODS Matched FFPE and fresh frozen samples from 50 meningiomas underwent RNA extraction for concordance testing using a custom Nanostring gene expression panel comprised of 34 meningioma genes and 7 housekeeping genes. Matched Nanostring gene expression profiling and RNA-sequencing was available from 173 fresh frozen meningiomas. Nanostring batch, machine, and technician variability was tested on 10 FFPE meningiomas using 2 independent batches of biomarker reagents that were processed at 2 independent laboratories. To study intra-tumor heterogeneity, 68 spatially distinct meningioma biopsies obtained under stereotactic guidance from 13 tumors were analyzed using the Nanostring gene expression biomarker. RESULTS Matched FFPE and fresh frozen meningioma samples (N=50) demonstrated high gene expression concordance (Pearson R=0.89, F-test P&amp;lt; 2.2e-16) and risk score concordance (R=0.78, F-test P&amp;lt; 1.8e-11, residual standard error 0.12). The biomarker achieved high performance on FFPE samples (local freedom from recurrence [LFFR] c-index 0.75±SEM 0.05, 5y LFFR AUC 0.84, 95% interval 0.67-0.96). Test-retest concordance on FFPE samples (N=10) across independent reagent batches, machines, and technicians was high (gene expression concordance: R=0.97; risk score concordance R=0.94). Transcript counts were concordant across Nanostring and RNA sequencing approaches (N=173 frozen samples, R=0.90). Stereotactic intra-operative sampling (N=68 samples from 13 patients) revealed low levels of intra-tumor heterogeneity (median inter-quartile risk score within tumor: 0.10±0.01). CONCLUSIONS We demonstrate analytical reproducibility and robustness of a gene expression biomarker predicting meningioma outcomes and radiotherapy responses in FFPE and frozen samples across multiple conditions and platforms.
EXTH-24. FILAMENTOUS PHAGE AS A NANOTHERANOSTIC FOR THE DETECTION, IMAGING, AND TREATMENT OF GLIOMAS
Authors: Fred Lam, Uyanga Tsedev, Angela Belcher
Journal: Neuro-Oncology (2022)

Abstract Current standard of care treatment for gliomas includes maximal safe surgical resection followed by concurrent chemoradiation, however, the diffuse infiltrative nature of gliomas present certain challenges for neurosurgeons to clearly visualize tumor tissue under conventional white light during microsurgical resection. Fluorescence-guided surgical techniques have been recently introduced to help surgeons better visualize tumor tissue under the operating microscope. Fluorescent dyes conjugated to nanoscale materials that are functionalized with glioma-targeting peptide sequences, such as the 39 amino acid chlorotoxin (CTX) peptide sequence, have demonstrated clinical efficacy in recognizing microscopic tumor cells during surgeries. M13 bacteriophage (phage) are versatile, genetically tunable nanocarriers that have been recently adapted for use as theranostic platforms. Applying p3 capsid CTX fusion with a unique “inho” circular single-stranded DNA (cssDNA) gene packaging system, we produced miniature CTX inho (CTX-inho phage particles with a minimum length of 50 nm that can target intracranial orthotopic patient-derived glioblastoma tumors in the brains of mice. Systemically-administered indocyanine green-conjugated CTX-inho phage accumulated in brain tumors, facilitating short-wave infrared detection. Furthermore, we show that our inho phage can carry cssDNA that are transcriptionally active when delivered to GBM22 glioma cells in vitro. The ability to modulate the capsid display, surface loading, phage length, and cssDNA gene content makes the recombinant M13 phage particle an ideal nanotheranostic platform for neuro-oncological applications.
INNV-28. A PILOT STUDY EVALUATING THE FEASIBILITY OF USING AN ULTRA-FAST DIGITAL CONFOCAL MICROSCOPY SCANNER FOR REAL-TIME INTRA-OPERATIVE BRAIN TUMOUR DIAGNOSIS
Authors: William Bolton, Piravin Ramakrishnan, Dharsshini Reveendran, Arundhati Chakrabarty, Ryan Mathew
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Real-time intra-operative brain tumour tissue analysis in the operating room (OR) can shorten turnaround times and facilitate repeated sampling; the latter can improve diagnostic accuracy and guide resection to maximise extent. We evaluated the feasibility of using an ultra-fast confocal microscopy scanner (Histolog®, SamanTree Medical SA) in the OR for real-time intra-operative brain tumour tissue diagnosis. This study is the first use of Histolog® on primary human brain tissue globally. METHODS An observational pilot study with varying brain tumour types was conducted in a tertiary UK brain tumour centre. Multiple, freshly excised tissue samples were stained with Acridine Orange, and images captured within 60 seconds on Histolog® in the OR in parallel to current diagnostic pathways. A Consultant Neuropathologist performed a blinded correspondence assessment between Histolog® and current gold standard histopathology. Qualitative logging of diagnostic features was performed. RESULTS Cases studied (n=12) included glioma, metastasis, meningioma, schwannoma, and pituitary adenoma. Concordance between Histolog® and traditional (frozen section) intra-operative histopathological diagnosis was 83% (10/12 cases). One Histolog® case demonstrated superior diagnostic accuracy to frozen section. Histolog® images demonstrated specific diagnostic features such as clusters of cohesive epithelioid cells (metastatic carcinoma), sheet-like variably cellular and pleomorphic cells (gliomas), diffuse sheet-like monomorphic round nuclei (pituitary adenoma), elongated spindle cells (schwannoma), and nodular architecture and oval nuclei (meningioma). DISCUSSION Ultra-fast confocal microscopy scanning with Histolog® is feasible in the OR and Histolog® image resolution is adequate to identify histopathological features necessary for intra-operative brain tumour diagnosis. Training and clinico-radiological details are important in minimising discordance. A larger study with greater numbers and tumour types will now be performed to define an optimal scanning protocol and determine the strengths and limitations of the technology. Future studies should investigate the effect of real-time margin zone analysis on extending resection.
PATH-28. DIFFERENCES IN METHYLATION PROFILES BETWEEN LONG-TERM SURVIVORS AND SHORT-TERM SURVIVORS OF IDH WILD-TYPE GLIOBLASTOMA
Authors: Matthijs van der Meulen, Ronald Ramos, Mathew Voisin, Vikas Patil, Qingxia Wei, Olivia Singh, Seth Climans, Navya Kalidindi, Rosamarylin Or, Phideas Diamandis, David Munoz, Gelareh Zadeh, Warren Mason
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Patients with glioblastomas (GBM) have an overall survival (OS) of approximately 15 months. However, approximately 5% of patients survive much longer, with an OS of &amp;gt; 5 years. This study examines the differences in methylation profiles between long-term survivors ( &amp;gt; 5 years, LTS) and short-term survivors (&amp;lt; 1 year, STS) with an isocitrate dehydrogenase (IDH) wild-type GBM. METHODS In a multicenter retrospective analysis, we identified 25 long-term survivors with a histologically confirmed GBM. These were age and sex-matched to a short-term survivor. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of all IDH wild-type LTS vs STS were compared. RESULTS After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH wild-type GBMs, all with copy number gains of chromosome 7 and loss of chromosome 10. There were no significant differences between tumour purity or GBM subtype between LTS and STS. LTS had significantly increased MGMT promoter methylation (p = 0.01), and higher FGFR3-TACC3 (p = 0.03), compared to STS. STS had significantly more often a CDKN2A/B loss (p = 0.01) and higher levels of NF1 (p = 0.02), compared to LTS. There were no significant CpGs identified between LTS vs STS at an adjusted p-value of 0.05. Unadjusted analyses identified key pathways and biological processes involved in both LTS and STS. The top pathway in LTS was the Hippo signaling pathway and the Wnt pathway. The top pathway in STS was GPCR ligand binding and cell-cell signaling. CONCLUSION A small group of patients with IDH wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of long-term survivors compared to short-term survivors, our study highlights potential pathways involved in aggressive and senescent GBMs.
EXTH-50. IDENTIFYING TRIM11 AS A POTENTIAL THERAPEUTIC TARGET FOR MALIGNANT GLIOMAS
Authors: Kaijun Di, Daniela Abrams, Pratik Yadav, Bhaskar Das, Daniela Bota
Journal: Neuro-Oncology (2022)

Abstract TRIM11 (tripartite motif-containing protein 11) belongs to the TRIM/RBCC (the RING B-box coiled-coil) family of E3 ubiquitin ligases. Members of this family have been implicated in development, neurodegenerative diseases, cellular response to viral infection and cancer. Glioblastoma (GBM) is an aggressive infiltrative brain tumor with poor prognosis. Our previous work demonstrated that TRIM11 is over-expressed in high-grade gliomas and promotes proliferation, invasion, migration and tumor growth, suggesting TRIM11 is a target for malignant glioma treatment. Here we reported the effect of TRIM11 on GBM progression in vivo using immunocompromised mice intracranially implanted with GBM xenografts over-expressing TRIM11. The control group mice survived longer than the mice bearing TRIM11 over-expressing xenografts (P&amp;lt; 0.5), suggesting TRIM11 enhances tumor progression in vivo. The oncogenic effect of TRIM11 may be related to its influence on apoptosis pathway as a robust induction of poly (ADP-ribose) polymerase (PARP) was observed in TRIM11 over-expressing GBM cells. PARP could repair DNA damage caused by UV light, radiation, and certain anticancer drugs, etc. Blocking PARP may prevent cancer cells from repairing their damaged DNA, causing them to die. Temozolomide (TMZ) is a standard-of-care chemotherapeutic agent for GBM through alkylating/methylating DNA, leading to DNA damage and death of tumor cells. TRIM11 over-expressing GBM cells were found more resistant to TMZ and showed a higher survival rate compared to parental cells, indicating that TRIM11 might be a therapeutic target for GBM. Based on homology modeling we designed and synthesized small library of TRIM11 inhibitors, and identified one compound (BT# 592) significantly inhibited the growth of GBM cells in a dose-dependent manner, implicating that TRIM11 inhibitors may serve as novel agents for malignant glioma treatment. We are in the process to develop more active compounds using SAR studies to identify hit-to-lead compounds as potential therapeutics for GBM.
CTIM-27. AUTOLOGOUS TUMOR LYSATE-LOADED DENDRITIC CELL VACCINATION IMPROVES SURVIVAL IN PATIENTS WITH NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA: SURVIVAL RESULTS FROM A PHASE 3 TRIAL
Authors: Linda M Liau, Keyoumars Ashkan, Steven Brem, Jian Campian, John Trusheim, Fabio Iwamoto, David Tran, George Anstass, Charles Cobbs, Jason Heth, Michael Salacz, Stacy D'Andre, Robert Aiken, Yaron Moshel, JooYeon Nam, Clement Pillainayagam, Stephanie Wagner, Kevin Walter, Rekha Chaudary, Samuel Goldlust, Ian Lee, Daniela Bota, Heinrich Elinzano, Jai Grewal, Kevin Lillehei, Tom Mikkelsen, Tobias Walbert, Steve Abram, Andrew Brenner, Matthew Ewend, Simon Khagi, Darren Lovick, Jana Portnow, Lyndon Kim, William Loudon, Nina Martinez, Reid Thompson, David Avigan, Karen Fink, Francois Geoffroy, Pierre Giglio, Oleg Gligich, Dietmar Krex, Scott M Lindhorst, Jose Lutzky, Hans-Joerg Meisel, Minou Nadji-Ohl, Lhagva Sanchin, Andrew Sloan, Marnix Bosch
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p &amp;lt; 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.
NIMG-34. QUANTIFICATION OF GLYCOLYTIC FLUX REDUCTION IN RECURRENT GLIOBLASTOMA AFTER EGFR INHIBITION USING MOLECULAR MR-PET
Authors: Benjamin Ellingson, David Nathanson, Jingwen Yao, Akifumi Hagiwara, Catalina Raymond, Noriko Salamon, Whitney Pope, Albert Lai, Phioanh L Nghiemphu, Timothy Cloughesy
Journal: Neuro-Oncology (2022)

Abstract In recently published work, we demonstrated that acute inhibition of the EGFR – the most frequently altered oncogene in GBM – can rapidly reduce glycolysis in a subset of GBM. To quantify this effect, we propose a new combination metabolic MR-PET imaging biomarker that combines 18F-FDG PET, DSC perfusion MRI, diffusion MRI, and pH- and oxygen-sensitive amine CEST-SAGE-EPI. Specifically, this “glycolytic index” or GI, can be defined as elevated glucose uptake (18F-FDG standard uptake value), elevated tumor acidity (MTRasym@3ppm), and lower oxygen utilization (relative cerebral metabolic rate of oxygen, rCMRO2, defined as R2’ x rCBF/rCBV from oxygen-sensitive SAGE-EPI and DSC perfusion), normalized to cell density (using ADC from diffusion MRI). In the current study, we explored the use of Tagrisso® (Osimertinib or AZD9291), which has very high brain to plasma ratios (&amp;gt; 1) and has proven effective in CNS metastasis of EGFR mutant lung cancer, as a potential treatment for EGFR amplified recurrent GBM. We have conducted a clinical trial (NCT03732352) to determine whether we observe similar metabolic imaging changes in EGFR mutated or amplified recurrent glioblastoma patients after treatment with osimertinib. Consistent with prior in vitro and in vivo results, treated patients exhibited a reduced glycolytic flux as indicated by reduction in 18F-FDG PET uptake (-3% change in SUV), tumor acidity (-19% change in MTRasym@3ppm) on pH-weighted CEST MRI, and glycolytic index (GI) (-25% change) in EGFR amplified recurrent GBM within 24 hours of treatment. Preliminary data suggests early change in GI correlates with and predicts both PFS (Pearson correlation, R2=0.3463, P=0.0441; Log-rank, P=0.0467) and OS (R2=0.6368, P=0.0019; Log-rank, P=0.0192). These preliminary data establish the scientific premise that a “glycolytic index” created using 18F-FDG PET, DSC perfusion, diffusion MRI, and pH- and oxygen-weighted amine CEST-SAGE-EPI may be an important tool for quantifying and visualizing glycolytic flux in GBM.
DDEL-01. ANIMAL STUDIES WITH A NEW CNS DRUG DELIVERY DEVICE TO EFFECTIVELY TREAT LEPTOMENINGEAL CARCINOMATOSIS PATIENTS
Authors: Priya Kumthekar, Hector Benatti, Toloo Taghian, William B Gormley, Seema Nagpal, William C Baker, Rajan Patel, Emma Brown, Marcie Glicksman, Heather Gray-Edwards
Journal: Neuro-Oncology (2022)

Abstract Background Appropriate drug distribution is needed for effective treatment of brain metastases and leptomeningeal carcinomatosis. Lack of proper drug bioavailability in the CNS contributes to the poor outcome in these patients. EnClear Therapies has developed a device delivering intrathecal therapeutics utilizing the active control of CSF flow through an external pump. Herein, we look at intrathecal drug delivery of methotrexate with EnClear’s system and its impact of drug concentration in sheep and non-human primates. METHODS The EnClear device utilizes two implantable catheters (intracranial in the ventricular system and lumbar thecal sac) and an extracorporeal pump that controls the speed and direction of CSF flow. Software monitors the output from sensor arrays for pressure, respiration, and heart rate. Gadolinium and MRI were used to determine the CSF flow characteristics. Administration of Methotrexate via the EnClear system was compared to current two standards of delivery, intracerebroventricular or lumbar intrathecal administration. Methotrexate levels were measured with Liquid Chromatography/Mass Spectrometry in CSF, blood, and multiple CNS and peripheral tissues. RESULTS There was a two-fold increase in methotrexate levels in multiple regions of the brain including deeper brain structures including the striatum using the EnClear's system, compared to traditional lumbar intrathecal and intracerebroventricular delivery. Higher peak levels of methotrexate were reached in the CSF with the use of EnClear’s system, with simultaneous reduction in the peripheral nerves and systemic tissues – a potential source of toxicity. Conclusions In large animal studies, the EnClear device has for the first time, demonstrated increased brain parenchymal drug levels via intrathecal delivery. In addition to the drug parenchyma, drug delivery with this novel device has shown improved distribution throughout CNS and leptomeninges as compared to traditional intrathecal drug delivery and decreased peripheral distribution.